N-[phenyl (piperidin-2-yl) methyl]benzamide derivatives, preparation thereof, and use thereof in therapy

ABSTRACT

This invention discloses and claims a compound of general formula (I) 
                         
in which R 1  represents either a hydrogen atom, or an optionally substituted alkyl group, or a cycloalkylalkyl group, or an optionally substituted phenylalkyl group, or an alkenyl group, X represents a hydrogen atom or one or more substituents chosen from halogen atoms and trifluoromethyl, alkyl and alkoxy groups, R 2  represents one or more substituents chosen from halogen atoms, optionally substituted alkoxy and optionally substituted amino. The compounds of this invention exhibit therapeutic utility.

This application is a continuation of International application No.PCT/FR2003/002,356, filed Jul. 25, 2003; which claims the benefit ofpriority of French Patent Application No. 02/09,588, filed Jul. 29,2002, both of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to a series ofN-[phenyl(piperidin-2-yl)methyl]benzamide derivatives, their preparationand their application in therapy.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the general formula (I)

in which

-   R₁ represents either a hydrogen atom, or a linear or branched    (C₁–C₇)alkyl group optionally substituted with one or more fluorine    atoms, or a (C₃–C₇)cycloalkyl-(C₁–C₃)alkyl group, or a    phenyl(C₁–C₃)alkyl group optionally substituted with one or two    methoxy groups, or a (C₂–C₄)alkenyl group, or a (C₂–C₄)alkynyl    group,-   X represents a hydrogen atom or one or more substituents chosen from    halogen atoms and trifluoromethyl, linear or branched (C₁–C₄)alkyl    and (C₁–C₄)alkoxy groups,-   R₂ represents one or more substituents chosen from halogen atoms,    from the groups of general formula OR₃ in which R₃ represents a    hydrogen atom, a (C₁–C₄)alkyl group, a phenyl(C₁–C₃)alkyl group, or    a group of general formula (CH₂)_(n)—NR₄R₅ in which n represents the    number 2, 3 or 4 and R₄ and R₅ each represent, independently of each    other, a hydrogen atom or a (C₁–C₄)alkyl group or form, with the    nitrogen atom carrying them, a pyrrolidine, piperidine or morpholine    ring, and from the amino groups of general formula NR₆R₇ in which R₆    and R₇ each represent, independently of each other, a hydrogen atom    or a (C₁–C₄)alkyl group, a phenyl group or a phenyl(C₁–C₃)alkyl    group, or form, with the nitrogen atom carrying them, a pyrrolidine,    piperidine or morpholine ring.

The compounds of general formula (I) may exist in the form of the threoracemate (1R,2R; 1S,2S) or in the form of enantiomers (1R,2R) or(1S,2S); they may exist in the form of free bases or of addition saltswith acids.

DETAILED DESCRIPTION OF THE INVENTION

Compounds having a structure which is analogous to that of the compoundsof the invention are described in U.S. Pat. No. 5,254,569 as analgesics,diuretics, anticonvulsants, anesthetics, sedatives, cerebroprotectiveagents, by a mechanism of action on the opiate receptors. Othercompounds having an analogous structure are described in PatentApplication EP 0499995 as 5-HT₃ antagonists which are useful in thetreatment of psychotic disorders, neurological diseases, gastricsyndromes, nausea and vomiting.

The preferred compounds of the invention are devoid of activity on theopiate or 5-HT3 receptors and exhibit a particular activity as specificinhibitors of the glycine transporters glyt1 and/or glyt2.

The compounds preferred as inhibitors of the glyt1 transporter are ofthe configuration (1S,2S) with R₂ representing one or more halogenatoms, while the compounds preferred as inhibitors of the glyt2transporter are of the configuration (1R,2R) with R₂ representing one ormore halogen atoms and an amino group of general formula NR₆R₇.

The compounds of general formula (I) in which R₁ is different from ahydrogen atom, may be prepared by a method illustrated by scheme 1 whichfollows.

A diamine of general formula (II), in which R₁ and X are as definedabove (with R₁ different from a hydrogen atom), is coupled to anactivated acid or an acid chloride of general formula (III) in which Yrepresents an activated OH group or a chlorine atom and R₂ is as definedabove, using methods known to persons skilled in the art.

The diamine of general formula (II) may be prepared by a methodillustrated by scheme 2 which follows.

The Weinreb amide of formula (IV) is reacted with the phenyllithiumderivative of general formula (V), in which X is as defined above, in anethereal solvent such as diethyl ether, between −30° C. and roomtemperature; a ketone of general formula (VI) is obtained which isreduced to an alcohol with the threo configuration of general formula(VII) with a reducing agent such as K-Selectride® or L-Selectride®(potassium or lithium tri-sec-butylborohydride), in an ethereal solventsuch as tetrahydrofuran, between −78° C. and room temperature. Thecarbamate of general formula (VII) may then be reduced to a threoN-methylaminoalcohol of general formula (VIII) by the action of a mixedhydride such as lithium aluminum hydride, in an ethereal solvent such astetrahydrofuran, between room temperature and the reflux temperature.The threo alcohol of general formula (VIII) is then converted to a threointermediate of general formula (II) where R₁ represents a methyl group,in two steps: the alcohol functional group is first of all converted toa leaving group, for example a methanesulfonate group, by the action ofmethylsulfonyl chloride, in a chlorinated solvent such asdichloromethane, and in the presence of a base such as triethylamine,between 0° C. and room temperature, and then the leaving group isreacted with liquefied ammonia at −50° C., in an alcohol such asethanol, in a closed medium such as an autoclave, between −50° C. androom temperature.

It is also possible to deprotect the carbamate of general formula (VII)by means of a strong base such as aqueous potassium hydroxide, in analcohol such as methanol in order to obtain the threo amino alcohol ofgeneral formula (IX), and to then carry out an N-alkylation by means ofa halogenated derivative of formula R₁Z, in which R₁ is as definedabove, but different from a hydrogen atom, and Z represents a halogenatom, in the presence of a base such as potassium carbonate, in a polarsolvent such as N,N-dimethylformamide, between room temperature and 100°C. The alcohol of general formula (X) thus obtained is then treated asdescribed for the alcohol of general formula (VIII).

Another variant method, illustrated by scheme 3 which follows, may beused in the case where R₁ represents a methyl group and X represents ahydrogen atom. The pyridine oxime of formula (XI) is quaternized, forexample, by the action of methyl trifluoromethanesulfonate, in anethereal solvent such as diethyl ether, at room temperature. Thepyridinium salt thus obtained, of formula (XII), is then subjected tohydrogenation under a hydrogen atmosphere,

in the presence of a catalyst such as platinum oxide, in a mixture of analcohol and an aqueous acid such as ethanol and 1 N hydrochloric acid.The diamine of general formula (II) is obtained in which R₁ represents amethyl group and X represents a hydrogen atom in the form of a mixtureof the two diastereoisomers threo/erythro 9/1. It is possible to salifyit, for example, with oxalic acid, and then to purify it byrecrystallization of the oxalate formed from a mixture of an alcohol andan ethereal solvent such as methanol and diethyl ether, so as to obtainthe pure threo diastereoisomer (1R,2R; 1S,2S).

The compounds of general formula (II) in which R₁ represents a hydrogenatom may be prepared by the method illustrated by scheme 4 whichfollows.

Starting with the amine of general formula (XIII), in which X is asdefined above, a coupling is performed with an activated acid or an acidchloride, as described above, of general formula (III) according tomethods known to persons skilled in the art, in order to obtain thecompound of general formula (XIV). Finally, hydrogenation of the latteris performed, for example with hydrogen in the presence of a catalystsuch as 5% platinum on carbon, in an acidic solvent such as glacialacetic acid, so as to obtain a compound of general formula (I) in whichR₁ represents a hydrogen atom.

Another method consists in modifying a compound of general formula (I)in which R₁ represents either an optionally substituted phenylmethylgroup and in deprotecting the nitrogen of the piperidine ring, forexample, with an oxidizing agent or with a Lewis acid, such as borontribromide, or by hydrogenolysis, or an alkenyl group, preferably allyl,and in deprotecting the nitrogen with a Pd⁰ complex, in order to obtaina compound of general formula (I) in which R₁ represents a hydrogenatom.

Moreover, the chiral compounds of general formula (I) corresponding tothe enantiomers (1R,2R) or (1S,2S) of the threo diastereoisomer may alsobe obtained by separating the racemic compounds by high-performanceliquid chromatography (HPLC) on a chiral column, or by resolution of theracemic amine of general formula (II) by the use of a chiral acid, suchas tartaric acid, camphorsulfonic acid, dibenzoyltartaric acid orN-acetylleucine, by fractional and preferential recrystallization of adiastereoisomeric salt, from an alcohol type solvent, or alternativelyby enantioselective synthesis according to scheme 2 with the use of achiral Weinreb amide of formula (IV).

The racemic or chiral Weinreb amide of formula (IV), as well as theketone of general formula (VI), may be prepared according to a methodsimilar to that described in Eur. J. Med. Chem., 35, (2000), 979–988 andJ. Med. Chem., 41, (1998), 591–601. The phenyllithium compound ofgeneral formula (V) where X represents a hydrogen atom is commerciallyavailable. Its substituted derivatives may be prepared according to amethod similar to that described in Tetrahedron Lett., 57, 33, (1996),5905–5908. Also according to a method similar to that described inPatent Application EP-0366006. The amine of general formula (IX) inwhich X represents a hydrogen atom may be prepared in a chiral seriesaccording to a method described in U.S. Pat. No. 2,928,835. Finally, theamine of general formula (XIII) may be prepared according to a methodsimilar to that described in Chem. Pharm. Bull., 32, 12, (1984),4893–4906 and Synthesis, (1976), 593–595. All of the referencesdescribed herein are incorporated herein by reference in their entirety.

Some acids and acid chlorides of general formula (III) are commerciallyavailable or, when they are novel, they may be obtained according tomethods similar to those described in patents EP-0556672, U.S. Pat. No.3,801,636, and in J. Chem. Soc., (1927), 25, Chem. Pharm. Bull., (1992),1789–1792, Aust. J. Chem., (1984), 1938–1950 and J.O.C., (1980), 527.All of these references are incorporated herein by reference in theirentirety.

The examples which follow illustrate the preparation of a few compoundsof the invention. The elemental microanalyses, the IR and NMR spectraand the HPLC on a chiral column confirm the structures and theenantiomeric purities of the compounds obtained.

The numbers indicated in brackets in the headings of the examplescorrespond to those of the 1st column of the table given later.

In the names of the compounds, the dash “-” forms part of the word, andthe dash “-” only serves for splitting at the end of a line; it issuppressed in the absence of splitting, and should not be replacedeither by a normal dash or by a gap.

EXAMPLE 1 (COMPOUND NO. 65)2,3-Dichloro-N-[(1S)-[(2S)-1-methylpiperidin-2-yl]phenylmethyl]benzamideHydrochloride 1:1

1.1. 1,1-Dimethylethyl (2S)-2-benzoylpiperidine-1-carboxylate.

A solution of1,1-dimethylethyl(2S)-2-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate(11.8 g, 43.3 mmol) in 100 ml of anhydrous diethyl ether is introducedinto a 500 ml round-bottomed flask, under a nitrogen atmosphere, themedium is cooled to −23° C., 21.6 ml(43.2 mmol) of a 1.8 M phenyllithiumsolution in a 70/30 mixture of cyclohexane and diethyl ether are addeddropwise and the mixture is stirred at room temperature for 3 h.

After hydrolysis with a saturated aqueous sodium chloride solution, theaqueous phase is separated and it is extracted with ethyl acetate. Theorganic phase is dried over sodium sulfate, filtered, concentrated underreduced pressure and the residue is purified by chromatography on asilica gel column, eluting with a mixture of ethyl acetate andcyclohexane to obtain 4.55 g of a solid product.

Melting point: 123–125° C. [α]_(D) ²⁵=−25.4° (c=2.22; CH₂Cl₂) ee=97.2%,

1.2. 1,1-Dimethylethyl(1S)-2-[(2S)-hydroxy(phenyl)methyl]piperidine-1-carboxylate.

A solution of 1,1-dimethylethyl (2S)-2-benzoylpiperidine-1-carboxylate(4.68 g, 16.2 mmol) in 170 ml of anhydrous tetrahydrofuran is introducedinto a 500 ml round-bottomed flask, under a nitrogen atmosphere, thesolution is cooled to −78° C., 48.5 ml (48.5 mmol) of a 1 M solution ofL-Selectride® (lithium tri-sec-butylborohydride) in tetrahydrofuran areadded dropwise, and the mixture is stirred at room temperature for 5 h.

It is slowly hydrolyzed in the cold state with 34 ml of water and 34 mlof a 35% aqueous hydrogen peroxide solution, and the mixture is allowedto return to room temperature while it is being stirred for 2 h.

It is diluted with water and ethyl acetate, the aqueous phase isseparated, and extracted with ethyl acetate. After washing the combinedorganic phases, drying over sodium sulfate, filtration and evaporation,the residue is purified by chromatography on a silica gel column,eluting with a mixture of ethyl acetate and cyclohexane to obtain 4.49 gof a pale yellow oil.

[α]_(D) ²⁵=+63.75° (c=0.8; CH₂Cl₂) ee=97.8%.

1.3. (1S)-[(2S)-(1-methylpiperidin-2-yl)]phenylmethanol.

A solution of lithium aluminum hydride (2.96 g, 78.1 mmol) in 50 ml ofanhydrous tetrahydrofuran is introduced into a 200 ml two-necked flask,under a nitrogen atmosphere, the mixture is heated under reflux, 4.49 g(15.4 mmol) of a solution of 1,1-dimethylethyl(1S)-2-[(2S)-hydroxy(phenyl)methyl]piperidine-1-carboxylate in 35 ml oftetrahydrofuran are added and the mixture is kept under reflux for 3.5h.

It is cooled, it is slowly hydrolyzed with a 0.1 M solution of potassiumsodium tartrate and the mixture is kept stirred overnight.

It is filtered and the precipitate is rinsed with tetrahydrofuran, andthen the filtrate is concentrated under reduced pressure to obtain 2.95g of a colorless oily product.

1.4. (1S)-[(2S)-(1-methylpiperidin-2-yl)]phenylmethanamine.

A solution of (1S)-[(2S)-(1-methylpiperidin-2-yl)]phenylmethanol (2.95g, 14.4 mmol) and triethylamine (2 ml, 14.4 mmol) in 70 ml of anhydrousdichloromethane is introduced into a 250 ml round-bottomed flask, undera nitrogen atmosphere, the medium is cooled to 0° C., 1.1 ml (14.4 mmol)of methanesulfonyl chloride are added, the mixture is allowed to returnslowly to room temperature over 2 h and it is concentrated under reducedpressure.

Liquefied ammonia is introduced into an autoclave provided with magneticstirring and cooled to −50° C., a solution of crude methanesulfonateprepared beforehand in solution in 30 ml of absolute ethanol is added,the autoclave is closed and the stirring is maintained for 48 h.

The mixture is transferred to a round-bottomed flask, the solvent isevaporated under reduced pressure, and the amine is isolated in the formof an oily product which is used as it is in the next step.

1.5.2,3-Dichloro-N-[(1S)-[(2S)-1-methylpiperidin-2-yl]phenylmethyl]benzamidehydrochloride 1:1.

A solution of 2,3-dichlorobenzoic acid (0.5 g, 2.6 mmol),1-([3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.5 g,2.6 mmol) and 1-hydroxybenzotriazole (0.35 g, 2.6 mmol) in 10 ml ofdichloromethane is introduced into a 50 ml round-bottomed flask and themixture is stirred at room temperature for 30 min.

A solution of (1S)-[(2S)-(1-methylpiperidin-2-yl)]phenylmethanamine(0.53 g, 2.5 mmol) in a few ml of dichloromethane is added to the abovemixture and the stirring continued for 5 h.

The mixture is treated with water and extracted several times withdichloromethane. After washing the organic phases with water and thenwith a 1N aqueous sodium hydroxide solution, drying over magnesiumsulfate, filtration and evaporation of the solvent under reducedpressure, the residue is purified by chromatography on a silica gelcolumn, eluting with a mixture of dichloromethane and methanol. 0.52 gof oily product is obtained which is isolated in hydrochloride form froma 0.1N hydrochloric acid solution in propan-2-ol.

0.5 g of hydrochloride is finally isolated in the form of a white solid.

Melting point: 124–126° C. [α]_(D) ²⁵=+66.3° (c=0.58; CH₃OH).

EXAMPLE 2 (COMPOUND NO. 55)4-Amino-3,5-dichloro-N-[(1R)-[(2R)-1-methylpiperidin-2-yl]phenylmethyl]benzamideHydrochloride 1:1

2.1. 2-(Benzyloxyiminophenylmethyl)-1-methylpyridiniumtrifluoromethanesulfonate

17.4 ml(120 mmol) of methyl trifluoromethanesulfonate are added dropwiseat 0° C. to a suspension of 35 g (120 mmol) ofphenyl(pyridin-2-yl)methanone O-benzyloxime in 200 ml of diethyl ether,and the mixture is stirred at room temperature for 3 h.

The precipitate formed is recovered by filtration and it is dried underreduced pressure to obtain 49 g of product, which product is used as itis in the next step.

2.2. threo-(1-Methylpiperidin-2-yl)phenylmethanamine ethanedioate 2:1.

A solution of 2-(benzyloxyiminophenylmethyl)-1-methylpyridiniumtrifluoromethanesulfonate (14.8 g, 31.89 mmol) and 0.74 g of platinumoxide in 50 ml of ethanol and 50 ml of 1 N hydrochloric acid is placedin a Parr flask, and hydrogenation is performed for 5 h.

The ethanol is evaporated under reduced pressure, the residue isextracted with dichloromethane, the aqueous phase is separated, asolution of ammonia is added thereto and it is extracted withdichloromethane. After washing the combined organic phases, drying oversodium sulfate, filtration and evaporation of the solvent under reducedpressure, 6.7 g of an oily product comprising 10% of erythrodiastereoisomer are obtained.

The ethanedioate is prepared by dissolving the above isolated 6.7 g ofbase in methanol, and by the action of two equivalents of ethanedioicacid dissolved in the minimum amount of methanol.

The salt obtained is purified by recrystallization from a mixture ofmethanol and diethyl ether to isolate 4.7 g of pure ethanedioate of thethreo diastereoisomer.

Melting point: 156–159° C.

2.3. (1R)-[(2R)-(1-methylpiperidin-2-yl)]phenylmethanamine.

A solution of threo-(1-methylpiperidin-2-yl)phenylmethanamine (80 g, 390mmol) in 300 ml of methanol, and a solution of N-acetyl-D-leucine (68 g,390 mmol) in 450 ml of methanol are introduced into a 4 l round-bottomflask. The solution is concentrated under reduced pressure and theresidue is recrystallized from 1100 ml of propan-2-ol to obtain 72 g ofsalts of (1R)-[(2R)-(1-methylpiperidin-2-yl)]phenylmethanamine.

The recrystallization is repeated three more times to obtain 15 g ofadditional salt of(1R)-[(2R)-(1-methylpiperidin-2-yl)]phenylmethanamine.

Melting point: 171.5° C. [α]_(D) ²⁵=−11° (c=1; CH₃OH) ee>99%.

2.4.4-Amino-3,5-dichloro-N-[(1R)-[(2R)-1-methylpiperidin-2-yl]phenylmethyl]-3,5-dichlorobenzamide.Hydrochloride 1:1.

Employing the procedure described in step 1.6 of Example 1 above, andstarting with 2.18 g (11.65 mmol) of 4-amino-3,5-dichlorobenzoic acid,2.23 g (10.6 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1.41 g (10.6 mmol) of 1-hydroxybenzotriazole and 2.16 g(10.6 mmol) of (1R)-[(2R)-methylpiperidin-2-yl]phenylmethanamine, 3.92 gof the title compound are obtained in base form.

The hydrochloride thereof is prepared using a 0.1 N hydrochloric acidsolution in propan-2-ol to obtain 3.94 g of the hydrochloride in theform of a white solid.

Melting point: 250–260° C. [α]_(D) ²⁵=+24.5° (c=0.9; CH₃OH).

EXAMPLE 3 (COMPOUND NO. 59)3,5-Dichloro-N-[(1-methylpiperidin-2-yl)phenylmethyl]-4-(pyrrolidin-1-yl)benzamideHydrochloride 1:1

3.1. 3,5-Dichloro-4-fluorobenzoic acid.

A solution of 3,5-dichloro-4-fluoro[(trifluoromethyl)benzene] (5 g,21.46 mmol) in 10 ml of concentrated sulfuric acid is introduced into anautoclave and the solution is heated at 120° C. overnight.

After cooling, the mixture is taken up in water, the precipitate formedis recovered by filtration and it is dried under reduced pressure.

The title acid is quantitatively obtained, which acid is used as it isin the next step.

3.2. 3,5-Dichloro-4-(pyrrolidin-1-yl)benzoic acid.

1 g (4.8 mmol) of 3,5-dichloro-4-fluorobenzoic acid, 1.56 g (4.8 mmol)of cesium carbonate and 1 ml(12 mmol) of pyrrolidine in solution in 5 mlof dimethyl sulfoxide are introduced into a 100 ml round-bottom flaskand the mixture is heated at 125° C. overnight.

After cooling, it is hydrolyzed with concentrated hydrochloric acid, theprecipitate formed is recovered by filtration and it is dried underreduced pressure to obtain 0.65 g of title acid.

3.3.3,5-Dichloro-N-[(1-methylpiperidin-2-yl)phenylmethyl]-4-(pyrrolidin-1-yl)benzamidehydrochloride 1:1.

Using the procedure described in step 1.6 of Example 1 above, andstarting with 0.5 g (2 mmol) of 3,5-dichloro-4-(pyrrolidin-1-yl)benzoicacid, 0.35 g (1.82 mmol) of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 0.25 g(1.82 mmol) of 1-hydroxybenzotriazole and 0.37 g (1.82 mmol) ofthreo-(1-methylpiperidin-2-yl)]phenylmethanamine, 0.1 g of product isobtained in base form.

The hydrochloride thereof is prepared from a 0.1 N hydrochloric acidsolution in propan-2-ol.

0.85 g of hydrochloride is finally isolated in the form of a whitesolid.

Melting point: 157–159° C.

EXAMPLE 4 (COMPOUND NO. 76)2,3-Dichloro-N-[(S)-phenyl[(2S)-piperidin-2-yl]methyl]benzamide

4.1. (S)-Phenyl[(2S)-piperidin-2-yl]methanol.

A solution of 2.0 g (6.9 mmol) of 1,1-dimethylethyl(1S)-2-[(2S)-hydroxy(phenyl)methyl)-piperidine-1-carboxylate (obtainedaccording to the procedure described in step 1.2 of Example 1) in 40 mlof methanol is placed in a 250 ml round-bottom flask, an aqueouspotassium hydroxide solution prepared from 2 g of potassium hydroxidepellets and 20 ml of water is added, and the mixture is heated underreflux for 2 h.

It is cooled, the solvent is evaporated off under reduced pressure,water is added and the mixture is extracted several times withdichloromethane. After washing the combined organic phases, drying onmagnesium sulfate, filtration and evaporation of the solvent underreduced pressure, 1 g of a white solid is obtained.

Melting point: 148–150° C. [α]_(D) ²⁵=+38.4° (c=0.98; CHCl₃).

4.2. (S)-[(2S)-1-Allylpiperidin-2-yl](phenyl)methanol.

2.6 g (13.58 mmol) of (S)-phenyl[(2S)-piperidin-2-yl]methanol and 100 mlof acetonitrile are introduced into a 500 ml round-bottom flask providedwith magnetic stirring and purged with argon. 2.8 g of potassiumcarbonate and 1.4 ml (1.2 eq.) of allyl bromide are then added to thesuspension obtained, and the stirring is maintained at 25° C. for 6 h.

100 ml of water and 100 ml of ethyl acetate are added, the aqueous phaseis separated, it is extracted three times with 50 ml of ethyl acetate,the combined organic phases are washed with 100 ml of water and then 100ml of a saturated aqueous sodium chloride solution, dried over sodiumsulfate, filtered and the solvent is evaporated off under reducedpressure.

3 g of a yellow oil are obtained, which oil is purified bychromatography on a silica gel column (120 g, elution gradient from 2%to 10% of methanol in dichloromethane over 30 min).

2.7 g of product are isolated in the form of a yellow oil.

4.3. (S)-[(2S)-1-Allylpiperidin-2-yl](phenyl)-methanamine

2.7 g (11.67 mmol) of (S)-[(2S)-1-allylpiperidin-2-yl](phenyl)methanoland 1.62 ml of triethylamine in 80 ml of anhydrous dichloromethane areintroduced into a 250 ml round-bottom flask, under a nitrogenatmosphere, the medium is cooled to 0° C., 0.9 ml of methylsulfonylchloride is added, the mixture is allowed to return slowly to roomtemperature over 2 h and it is concentrated under reduced pressure.

Liquefied ammonia is introduced into an autoclave provided with magneticstirring and cooled to −50° C., a solution of crude methanesulfonatepreviously prepared in solution in 30 ml of absolute ethanol is added,the autoclave is closed and the stirring is maintained for 48 h.

The mixture is poured into a round-bottom flask, it is concentratedunder reduced pressure and 1.5 g of amine are isolated in the form of anoily product which is used as it is in the next step.

4.4.N-[(S)-[(2S)-1-Allylpiperidin-2-yl](phenyl)-methyl]-2,3-dichlorobenzamide.

5 ml of dichloromethane, 0.13 g (0.68 mmol) of 2,3-dichlorobenzoic acid,0.13 g (0.68 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride and 0.085 g of dimethylaminopyridine are successivelyintroduced into a 10 ml round-bottom flask, and the mixture is stirredat room temperature for 30 min.

0.18 g of (S)-[(2S)-1-allylpiperidin-2-yl](phenyl)methanamine insolution in a few ml of dichloromethane is added and the stirring iscontinued for 24 h. 5 ml of water are added, the mixture is filtered ona Whatman® cartridge (PTFE) and purified directly on a cartridge of 10 gof silica, eluting with a 98/2 to 90/10 mixture of dichloromethane andmethanol.

0.18 g of base is isolated in the form of a colorless oil.

4.5. 2,3-Dichloro-N-[(S)-phenyl[(2S)-piperidin-2-yl]methyl]benzamide.

0.21 g (3 eq.) of 1,3-dimethylbarbituric acid in solution in 3 ml ofanhydrous dichloromethane is introduced into a 10 ml round-bottom flaskprovided with mechanical stirring, under an argon atmosphere, 0.005 g(0.01 eq.) of tetrakis(triphenylphosphine)-palladium (0) is added andthe mixture is heated at 30° C.

A solution of 0.18 g (0.3 mmol) ofN-[(S)-[(2S)-1-allylpiperidin-2-yl](phenyl)methyl]-2,3-dichlorobenzamidein 1 ml of dichloromethane is added and the mixture is kept stirring for24 h.

3 ml of a saturated aqueous sodium hydrogen sulfate solution are added,the mixture is filtered on a Whatman® cartridge (PTFE) and purifieddirectly on a cartridge of 10 g of silica, eluting with dichloromethanecontaining 0.4% of a 33% ammonia solution.

0.1 g of base is isolated, which base is salified with a 0.1 Nhydrochloric acid solution in propan-2-ol.

0.076 g of hydrochloride is obtained which is purified in a reversedphase on an XTerra® MS C18 column (pH 10).

0.037 g of base is finally isolated in the form of white crystals.

Melting point: 156–158° C.

The table that follows lists the chemical structures and the physicalproperties of a few compounds of the invention.

In the “R₂” column of this table, “piperid” denotes a piperidin-1-ylgroup, “pyrrolid” denotes a pyrrolidin-1-yl group and “morphol” denotesa morpholin-4-yl group.

In the “Salt” column, “-” denotes a compound in base state and “HCl”denotes a hydrochloride; the acid:base molar ratio is indicatedopposite.

The optical rotations of the optically pure compounds are as follows

No. Stereochemistry [α]_(D) ²⁰ (°, CH₃OH) 41 threo (1S, 2S) −73.3 c =0.225 55 threo (1R, 2R) +24.5 c = 0.9 64 threo (1S, 2S) +13.2 c = 0.8465 threo (1S, 2S) +66.3 c = 0.58 71 threo (1S, 2S) +73.9 c = 0.89 72threo (1R, 2R) −97.0 c = 1 74 threo (1R, 2R) −104.4 c = 1

No. Stereochemistry R₁ X R₂ Salt M.p. (° C.)  1 threo (1R,2R;1S,2S) CH₃H 3-OCH₃, 4-Cl — 159–161  2 threo (1R,2R;1S,2S) CH₃ H 3-I, 4-Cl —102–104  3 threo (1R,2R;1S,2S) CH₃ H 4-Cl — 149.5–150.5  4 threo(1R,2R;1S,2S) CH₃ H 3,5-Cl₂ HCl 1:1 152–154  5 threo (1R,2R;1S,2S) CH₃ H4-N(CH₃)₂ — 128–130  6 threo (1R,2R;1S,2S) CH₃ H 3,4-Cl₂ — 50–52  7threo (1R,2R;1S,2S) CH₃ H 3,4-(OCH₃)₂ HCl 1:1 68–70  8 threo(1R,2R;1S,2S) CH₃ H 3,4-F₂ HCl 1:1 62–64  9 threo (1R,2R;1S,2S) CH₃ H3-F HCl 1:1 36–38 10 threo (1R,2R;1S,2S) CH₃ H 3-Br HCl 1:1 116–118 11threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂, 4-OH — 266–268 12 threo (1R,2R;1S,2S)CH₃ H 3-N(CH₃)₂ HCl 1:1 87–88 13 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂,4-NH₂ — 170–171 14 threo (1R,2R;1S,2S) CH₃ H 3-Br, 4-OCH₃ HCl 1:1136–137 15 threo (1R,2R;1S,2S) CH₃ H 2,4,6-Cl₃ —  97–104 16 threo(1R,2R;1S,2S) CH₃ H 2,3-Cl₂ — 107–114 17 threo (1R,2R;1S,2S) CH₃ H 2-Cl— 126–130 18 threo (1R,2R;1S,2S) CH₃ H 2,4-Cl₂ — 138–142 19 threo(1R,2R;1S,2S) CH₃ H 2-Cl, 4-Br — 143–145 20 threo (1R,2R;1S,2S) CH₃ H2,5-Cl₂ — 133–134 21 threo (1R,2R;1S,2S) CH₃ H 2,6-Cl₂ — 138–143 22threo (1R,2R;1S,2S) CH₃ H 2,3,5-Cl₃ — 156–159 23 threo (1R,2R;1S,2S) CH₃H 2-NH₂, 3,5-Cl₂ HCl 1:1 186–188 24 threo (1R,2R;1S,2S) CH₃ H 2-Cl,5-NH₂ HCl 1:1 266–268 25 threo (1R,2R;1S,2S) CH₃ H 3-Cl, 4-NH₂ HCl 1:1164–166 26 threo (1R,2R;1S,2S) CH₃ H 3-NH₂, 4-Cl HCl 1:1 230–232 27threo (1R,2R;1S,2S) CH₃ H 2-Cl, 4-NH₂ HCl 1:1 254–256 28 threo(1R,2R;1S,2S) CH₃ H 2-NH₂, 4-Cl HCl 1:1 236–238 29 threo (1R,2R;1S,2S)CH₃ H 2-Cl, 3-NH₂ HCl 1:1 195–200 30 threo (1R,2R;1S,2S) CH₃ H 6-NH₂,2,5-Cl₂ HCl 1:1 267–268 31 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂,4-O(CH₂)₂piperid HCl 2:1 44–46 32 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂,4-O(CH₂)₃N(CH₃)₂ HCl 2:1 39–41 33 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂,4-O(CH₂)₂N(CH₃)₂ HCl 2:1 130–132 34 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂,4-O(CH₂)₂pyrrolid HCl 2:1 78–80 35 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂,4-O(CH₂)₂morphol HCl 2:1 166–168 36 threo (1R,2R;1S,2S) CH₃ H 2-Cl, 6-FHCl 1:1 266–268 37 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂, 4-N(CH₃)₂ HCl 1:1157–159 38 threo (1R,2R;1S,2S) CH₃ H 2-Cl, 5-I HCl 1:1 281–285 39 threo(1R,2R;1S,2S) CH₃ H 3,5-Cl₂, 4-NHCH₂CH₃ HCl 1:1 175–180 40 threo(1R,2R;1S,2S) CH₃ H 3-Cl, 4-I HCl 1:1 98–99 41 threo (1S,2S) CH₃ H3,5-Cl₂, 4-NH₂ — 176–177 42 threo (1R,2R;1S,2S) CH₃ H 2-I, 4-Cl —213–214 43 threo (1R,2R;1S,2S) CH₃ H 3-Cl, 4-OH HCl 1:1 194–195 44 threo(1R,2R;1S,2S) CH₃ H 3-Cl, 4-piperid HCl 1:1 270–272 45 threo(1R,2R;1S,2S) CH₃ H 2-OCH₃, 3,5-Cl₂ — 97–98 46 threo (1R,2R;1S,2S) CH₃ H2-Cl, 3,4-(OCH₃)₂ — 229–230 47 threo (1R,2R;1S,2S) CH₃ H 2-Br, 4-F —124–125 48 threo (1R,2R;1S,2S) CH₃ H 3-Cl, 4-pyrrolid HCl 1:1 154–156 49threo (1R,2R;1S,2S) CH₃ H 2-Br, 5-Cl — 156–157 50 threo (1R,2R;1S,2S)CH₃ H 2-Br — 202–203 51 threo (1R,2R;1S,2S) CH₃ H 2-Br, 4,5-(OCH₃)₂ —218–219 52 threo (1R,2R;1S,2S) CH₃ H 2-Cl, 3,6-F₂ — 52–53 53 threo(1R,2R;1S,2S) CH₃ H 3-Cl, 4-morphol HCl 1:1 158–162 54 threo(1R,2R;1S,2S) CH₃ H 3,5-Cl, 4-piperid HCl 1:1 154–163 55 threo (1R,2R)CH₃ H 3,5-Cl₂, 4-NH₂ HCl 1:1 250–260 56 threo (1R,2R;1S,2S) CH₃ H 2-I,3-Cl HCl 1:1 253–255 57 threo (1R,2R;1S,2S) CH₃ H 2-Cl, 3-I HCl 1:1297–298 58 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂, 4-NHC₆R₅ HCl 1:1 236–24059 threo (1R,2R;1S,2S) CH₃ H 3,5-Cl₂, 4-pyrrolid HCl 1:1 157–159 60threo (1R,2R;1S,2S) CH₃ H 2-Cl, 6-F HCl 1:1 271–272 61 threo(1R,2R;1S,2S) CH₃ H 2-Cl, 4,5-(OCH₃)₂ — 242–243 62 threo (1R,2R;1S,2S)CH₃ H 2-Cl, 4-F HCl 1:1 365–366 63 threo (1R,2R;1S,2S) CH₃ H 2-Br,5-OCH₃ — 213–214 64 threo (1S,2S) CH₃ H 3,5-Cl₂, 4-N(CH₃)₂ HCl 1:1158–168 65 threo (1S,2S) CH₃ H 2,3-Cl₂ HCl 1:1 124–126 66 threo(1R,2R;1S,2S) CH₃ H 3,5-(OCH₃)₂, 4-OCH₂C₆H₅ HCl 1:1 274–275 67 threo(1R,2R;1S,2S) CH₃ H 3,5-Cl₂, 4-OCH₂C₆H₅ HCl 1:1 165–175 68 threo(1R,2R;1S,2S) CH₃ H 3,5-Cl₂, 4-NHCH₂C₆H₅ HCl 1:1 165–175 69 threo(1R,2R;1S,2S) CH₃ H 2-Cl, 3-F HCl 1:1 115–116 70 threo (1R,2R;1S,2S) CH₃H 2-Cl, 5-F HCl 1:1 212–215 71 threo (1S,2S) CH₃ H 2-Cl, 4-F HCl 1:1123–125 72 threo (1R,2R) CH₃ H 2,5-Cl₂, 6-NH₂ HCl 1:1 66–67 73 threo(1R,2R;1S,2S) CH₃ H 2-Cl, 5-OCH₃, 6-NH₂ HCl 1:1 258–259 74 threo (1R,2R)CH₃ H 2-Cl, 5-OCH₃, 6-NH₂ HCl 1:1 138–139 75 threo (1R,2R;1S,2S) CH₃ H2,3-Cl₂, 6-NH₂ HCl 1:1 230–236 76 threo (1S,2S) H H 2,3-Cl₂ — — 156–158

The compounds of the invention were subjected to a series ofpharmacological trials which demonstrated their utility as substanceshaving therapeutic activity.

Study of the Transport of Glycine in SK-N-MC Cells Expressing the NativeHuman Transporter Glyt1.

The capture of [¹⁴C]glycine is studied in SK-N-MC cells (humanneuroepithelial cells) expressing the native human transporter glyt1 bymeasuring the radioactivity incorporated in the presence or in theabsence of the test compound. The cells are cultured in a monolayer for48 h in plates pretreated with fibronectin at 0.02%. On the day of theexperiment, the culture medium is removed and the cells are washed witha Krebs-HEPES ([4-(2-hydroxyethyl)piperiazine-1-ethanesulphonic acid)buffer at pH 7.4. After a preincubation of 10 min at 37° C. in thepresence either of buffer (control batch), or of test compound atvarious concentrations, or of 10 mM glycine (determination of thenonspecific capture), 10 μM [¹⁴C]glycine (specific activity 112mCi/mmol) are then added. The incubation is continued for 10 min at 37°C., and the reaction is stopped by 2 washes with a Krebs-HEPES buffer atpH 7.4. The radioactivity incorporated by the cells is then estimatedafter adding 100 μl of liquid scintillant and stirring for 1 h. Thecounting is performed on a Microbeta Tri-lux™ counter. The efficacy ofthe compound is determined by the IC₅₀, the concentration of thecompound which reduces by 50% the specific capture of glycine, definedby the difference in radioactivity incorporated by the control batch andthe batch which received the glycine at 10 mM.

The compounds of the invention, in this test, have an IC₅₀ of the orderof 0.001 to 10 μM.

Study Ex Vivo of the Inhibitory Activity of a Compound on the Capture of[¹⁴C]Glycine in Mouse Cortical Homogenate

Increasing doses of the compound to be studied are administered by theoral route (preparation by trituration of the test molecule in a mortarin a solution of Tween/Methocel™ at 0.5% in distilled water) or by theintraperitoneal route (dissolution of the test molecule in physiologicalsaline or preparation by trituration in a mortar in a solution ofTween/Methocel™ at 0.5% in water, according to the solubility of themolecule) to 20 to 25 g Iffa Crédo OF1 male mice on the day of theexperiment. The control group is treated with the vehicle. The doses inmg/kg, the route of administration and the treatment time are determinedaccording to the molecule to be studied.

After the animals have been humanely killed by decapitation at a giventime after the administration, the cortex of each animal is rapidlyremoved on ice, weighed and stored at 4° C. or frozen at −80° C. (inboth cases, the samples are stored for a maximum of 1 day). Each sampleis homogenized in a Krebs-HEPES buffer at pH 7.4 at a rate of 10 ml/g oftissue. 20 μl of each homogenate are incubated for 10 min at roomtemperature in the presence of 10 mM L-alanine and buffer. Thenonspecific capture is determined by adding 10 mM glycine to the controlgroup. The reaction is stopped by filtration under vacuum and theretained radioactivity is estimated by solid scintillation by countingon a Microbeta Tri-lux™ counter.

An inhibitor of the capture of [¹⁴C]glycine will reduce the quantity ofradioligand incorporated into each homogenate. The activity of thecompound is evaluated by its ED₅₀, the dose which inhibits by 50% thecapture of [¹⁴C]glycine compared with the control group.

The most potent compounds of the invention, in this test, have an ED₅₀of 0.1 to 5 mg/kg by the intraperitoneal route or by the oral route.

Study of the Transport of Glycine in Mouse Spinal Cord Homogenate

The capture of [¹⁴C]glycine by the transporter glyt2 is studied in mousespinal cord homogenate by measuring the radioactivity incorporated inthe presence or in the absence of the compound to be studied.

After the animals have been humanely killed (Iffa Crédo OF1 male miceweighing 20 to 25 g on the day of the experiment), the spinal cord ofeach animal is rapidly removed, weighed and stored on ice. The samplesare homogenized in a Krebs-HEPES([4-(2-hydroxyethyl)piperazine-1-ethanesulphonic acid) buffer, pH 7.4,at a rate of 25 ml/g of tissue.

50 μl of homogenate are preincubated for 10 min at 25° C. in thepresence of Krebs-HEPES buffer, pH 7.4 and of compound to be studied atvarious concentrations, or of 10 mM glycine in order to determine thenonspecific capture. The [¹⁴C]glycine (specific activity=112 mCi/mmol)is then added for 10 min at 25° C. at the final concentration of 10 μM.The reaction is stopped by filtration under vacuum and the radioactivityis estimated by solid scintillation by counting on a Microbeta Tri-lux™counter. The efficacy of the compound is determined by the concentrationIC₅₀ capable of reducing by 50% the specific capture of glycine, definedby the difference in radioactivity incorporated by the control batch andthe batch which received the 10 mM glycine.

The compounds of the invention in this test have an IC₅₀ of the order of0.001 to 10 μM.

Study Ex Vivo of the Inhibitory Activity of a Compound on the Capture of[¹⁴C]Glycine in Mouse Spinal homogenate

Increasing doses of the compound to be studied are administered by theoral route (preparation by trituration of the test compound in a mortar,in a solution of Tween/Methocel™ at 0.5% in distilled water) orintraperitoneal route (test compound dissolved in physiological saline,or triturated in a mortar, in a solution of Tween/Methocel™ at 0.5% indistilled water) to 20 to 25 g Iffa Crédo OF1 male mice on the day ofthe experiment. The control group is treated with the vehicle. The dosesin mg/kg, the route of administration, the treatment time and the humanekilling time are determined according to the compound to be studied.

After humanely killing the animals by decapitation at a given time afterthe administration, the spinal cords are rapidly removed, weighed andintroduced into glass scintillation bottles, stored on crushed ice orfrozen at −80° C. (in both cases, the samples are stored for a maximumof 1 day). Each sample is homogenized in a Krebs-HEPES buffer at pH 7.4,at a rate of 25 ml/g of tissue. 50 μl of each homogenate are incubatedfor 10 min at room temperature in the presence of buffer.

The nonspecific capture is determined by adding 10 mM glycine to thecontrol group.

The reaction is stopped by filtration under vacuum and the radioactivityis estimated by solid scintillation by counting on a Microbeta Tri-lux™counter.

An inhibitor of the capture of [¹⁴C]glycine will reduce the quantity ofradioligand incorporated in each homogenate. The activity of thecompound is evaluated by its ED₅₀, the effective dose which inhibits by50% the capture of [¹⁴C]glycine compared with the control group.

The best compounds of the invention have, in this test, an ED₅₀ of 1 to20 mg/kg, by the intraperitoneal route or by the oral route.

The results of the trials carried out on the compounds of the inventionhaving the configuration (1S,2S) and their threo racemates having theconfiguration (1R,2R; 1S,2S) in the general formula (I) of which R₂represents one or more halogen atoms show that they are inhibitors ofthe glycine transporter glyt1 which are present in the brain, this beingin vitro and ex vivo.

These results suggest that the compounds of the invention can be usedfor the treatment of behavioral disorders associated with dementia,psychoses, in particular schizophrenia (deficient form and productiveform) and acute or chronic extrapyramidal symptoms induced byneuroleptics, for the treatment of various forms of anxiety, panicattacks, phobias, obsessive-compulsive disorders, for the treatment ofvarious forms of depression, including psychotic depression, for thetreatment of disorders due to alcohol abuse or to withdrawal fromalcohol, sexual behavior disorders, food intake disorders, and for thetreatment of migraine.

The results of the trials carried out on the compounds of the inventionhaving the configuration (1R,2R) and their racemates having theconfiguration (1R,2R; 1S,2S) in the general formula (I) of which R₂represents both a halogen atom and an amino group NR₆R₇ show that theyare inhibitors of the glycine transporter glyt2, predominantly presentin the spinal cord, this being in vitro and ex vivo.

These results suggest that the compounds of the invention may be usedfor the treatment of painful muscular contractures in rheumatology andin acute spinal pathology, for the treatment of spastic contractures ofmedullary or cerebral origin, for the symptomatic treatment of acute andsubacute pain of mild to moderate intensity, for the treatment ofintense and/or chronic pain, of neurogenic pain and rebellious algia,for the treatment of Parkinson's disease and of Parkinsonian symptoms ofneurodegenerative origin or induced by neuroleptics, for the treatmentof primary and secondary generalized epilepsy, partial epilepsy with asimple or complex symptomatology, mixed forms and other epilepticsyndromes as a supplement to another antiepileptic treatment, or inmonotherapy, for the treatment of sleep apnea, and for neuroprotection.

Accordingly, the subject of the present invention is also pharmaceuticalcompositions containing an effective dose of at least one compoundaccording to the invention, in the form of a pharmaceutically acceptablebase or salt or solvate, and in the form of a mixture, whereappropriate, with suitable excipients.

The said excipients are chosen according to the pharmaceutical dosageform and the desired mode of administration.

The pharmaceutical compositions according to the invention may thus beintended for oral, sublingual, subcutaneous, intramuscular, intravenous,topical, intratracheal, intranasal, transdermal, rectal or intraocularadministration.

The unit forms for administration may be, for example, tablets, gelatincapsules, granules, powders, oral or injectable solutions orsuspensions, patches or suppositories. For topical administration, it ispossible to envisage ointments, lotions and collyria.

The said unit forms contain doses in order to allow a dailyadministration of 0.01 to 20 mg of active ingredient per kg of bodyweight, according to the galenic form.

To prepare tablets, there are added to the active ingredient, micronizedor otherwise, a pharmaceutical vehicle which may be composed ofdiluents, such as for example lactose, microcrystalline cellulose,starch, and formulation adjuvants such as binders,(polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like),flow-enhancing agents such as silica, lubricants such as magnesiumstearate, stearic acid, glyceryl tribehenate, sodium stearylfumarate.Wetting agents or surfactants, such as sodium lauryl sulfate, may alsobe added.

The techniques for production may be direct compression, drygranulation, wet granulation or hot-melt.

The tablets may be uncoated, coated, for example with sucrose, or coatedwith various polymers or other appropriate materials. They may bedesigned to allow rapid, delayed or prolonged release of the activeingredient by virtue of polymer matrices or specific polymers used inthe coating.

To prepare gelatin capsules, the active ingredient is mixed with dry(simple mixture, dry or wet granulation, or hot-melt), liquid orsemisolid pharmaceutical vehicles.

The gelatin capsules may be hard or soft, film-coated or otherwise, soas to have rapid, prolonged or delayed activity (for example for anenteric form).

A composition in syrup or elixir form or for administration in the formof drops may contain the active ingredient together with a sweetener,preferably calorie-free, methylparaben or propylparaben as antiseptic, aflavor modifier and a coloring agent.

The water-dispersible powder and granules may contain the activeingredient in the form of a mixture with dispersing agents or wettingagents, or dispersants such as polyvinylpyrrolidone, and with sweetenersand flavor corrigents.

For rectal administration, suppositories are used which are preparedwith binders which melt at rectal temperature, for example cocoa butteror polyethylene glycols.

For parenteral administration, there are used aqueous suspensions,isotonic saline solutions or sterile solutions for injection containingpharmacologically compatible dispersing agents and/or wetting agents,for example propylene glycol or butylene glycol.

The active ingredient may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives, oralternatively with a polymer matrix or with a cyclodextrin (patches,prolonged release forms).

The topical compositions according to the invention comprise a mediumcompatible with the skin. They may be provided in particular in the formof aqueous, alcoholic or aqueous-alcoholic solutions, gels, water-in-oilor oil-in-water emulsions having the appearance of a cream or of a gel,microemulsions, aerosols, or alternatively in the form of vesiculardispersions containing ionic and/or nonionic lipids. These galenic formsare prepared according to the customary methods in the fieldsconsidered.

Finally, the pharmaceutical compositions according to the invention maycontain, apart from a compound of general formula (I), other activeingredients which may be useful in the treatment of the disorders anddiseases indicated above.

Although the invention has been illustrated by certain of the precedingexamples, it is not to be construed as being limited thereby; butrather, the invention encompasses the generic area as hereinbeforedisclosed. Various modifications and embodiments can be made withoutdeparting from the spirit and scope thereof.

1. A compound, in the form of an enantiomer (1R,2R) or (1S,2S) or in theform of a threo diastereoisomer, corresponding to general formula (I)

wherein R₁ is either a hydrogen atom, or a linear or branched(C₁–C₇)alkyl group optionally substituted with one or more fluorineatoms, or a (C₃–C₇)cycloalkyl(C₁–C₃)alkyl group, or a phenyl(C₁–C₃)alkylgroup optionally substituted with one or two methoxy groups, or a(C₂–C₄)alkenyl group, or a (C₂–C₄)alkynyl group, X is a hydrogen atom orone or more substituents chosen from halogen atoms and trifluoromethyl,linear or branched (C₁–C₄)alkyl and (C₁–C₄)alkoxy groups, R₂ is one ormore substituents chosen from halogen atoms, from the groups of generalformula OR₃ in which R₃ represents a hydrogen atom, a (C₁–C₄)alkylgroup, a phenyl(C₁–C₃)alkyl group, or a group of general formula(CH₂)_(n)—NR₄R₅ in which n is an integer 2, 3 or 4 and R₄ and R₅ eachrepresent, independently of each other, a hydrogen atom or a(C₁–C₄)alkyl group or form, with the nitrogen atom carrying them, apyrrolidine, piperidine or morpholine ring, and from the amino groups ofgeneral formula NR₆R₇ in which R₆ and R₇ each represent, independentlyof each other, a hydrogen atom or a (C₁–C₄)alkyl group, a phenyl groupor a phenyl(C₁–C₃)alkyl group, or form, with the nitrogen atom carryingthem, a pyrrolidine, piperidine or morpholine ring; or said compound inthe form of a free base or of an addition salt with an acid.
 2. Thecompound as set forth in claim 1, wherein it has the configuration(1S,2S), with R₂ representing one or more halogen atoms.
 3. The compoundas set forth in claim 1, wherein it has the configuration (1R,2R) withR₂ representing one or more halogen atoms and an amino group of generalformula NR₆R₇.
 4. A pharmaceutical composition comprising a compound, inthe form of an enantiomer (1R,2R) or (1S,2S) or in the form of a threodiastereoisomer, in combination with a pharmaceutical excipient, whereinsaid compound is corresponding to general formula (I):

wherein R₁ is either a hydrogen atom, or a linear or branched(C₁–C₇)alkyl group optionally substituted with one or more fluorineatoms, or a (C₃–C₇)cycloalkyl(C₁–C₃)alkyl group, or a phenyl(C₁–C₃)alkylgroup optionally substituted with one or two methoxy groups, or a(C₂–C₄)alkenyl group, or a (C₂–C₄)alkynyl group, X is a hydrogen atom orone or more substituents chosen from halogen atoms and trifluoromethyl,linear or branched (C₁–C₄)alkyl and (C₁–C₄)alkoxy groups, R₂ is one ormore substituents chosen from halogen atoms, from the groups of generalformula OR₃ in which R₃ represents a hydrogen atom, a (C₁–C₄)alkylgroup, a phenyl(C₁–C₃)alkyl group, or a group of general formula(CH₂)_(n)—NR₄R₅ in which n is an integer 2, 3 or 4 and R₄ and R₅ eachrepresent, independently of each other, a hydrogen atom or a(C₁–C₄)alkyl group or form, with the nitrogen atom carrying them, apyrrolidine, piperidine or morpholine ring, and from the amino groups ofgeneral formula NR₆R₇ in which R₆ and R₇ each represent, independentlyof each other, a hydrogen atom or a (C₁–C₄)alkyl group, a phenyl groupor a phenyl(C₁–C₃)alkyl group, or form, with the nitrogen atom carryingthem, a pyrrolidine, piperidine or morpholine ring; or said compound inthe form of a free base or of an addition salt with an acid.
 5. Thecomposition as set forth in claim 4, wherein said compound has theconfiguration (1S,2S), with R₂ representing one or more halogen atoms.6. The composition as set forth in claim 4, wherein said compound hasthe configuration (1R,2R) with R₂ representing one or more halogen atomsand an amino group of general formula NR₆R₇.